Death of photoreceptors is a common endpoint of several retinal degenerative diseases and often eventually results in blindness. In many cases of the retinal degenerative disease retinitis pigmentosa (RP), mutations in rod photoreceptor genes result in rod photoreceptor dysfunction and subsequent cell death. The majority of mutations in Rhodopsin (RHO) that cause RP are associated with the autosomal dominant form (adRP). These mutations lead to activation of the unfolded protein response (UPR) in the rods, due to a mislocalization of the mutant protein. A number of strategies are currently being pursued to reduce the UPR in the rods, or to reduce the expression of the mutant allele using siRNA. An alternative approach to modulate rod gene expression is suggested by developmental studies. During retinal development the expression of a few key transcription factors regulates photoreceptor cell fate and further specification into rod and cone photoreceptors. One critical transcription factor in the specification of cone versus rod fate is Nrl. Mice with mutations in Nrl have a retina without rods, but an increase in the number of cones because the rod precursors become cones without the expression of Nrl. Conversely, overexpression of Nrl in cone precursors results in decreased cone gene expression and a transformation to rod photoreceptors.
A recent study showed that partial transdifferentiation of mature rods into cones by conditional knockout of Nrl can prevent retinal degeneration in a mouse model of recessive RP (Rho−/− mice). This reprogramming of rods into cone-like cells prevented their death and therefore any secondary cone cell death as well. The orphan nuclear receptor Nr2e3 (also known as photoreceptor nuclear receptor) is a direct target of Nrl and is expressed in postmitotic photoreceptors soon after the onset of Nrl expression. Nr2e3 has a dual role as a transcriptional suppressor and co-activator during retinal development. It is required for the suppression of cone gene expression, as evidenced by the findings that mice with targeted or spontaneous mutations in Nr2e3 have increased expression of cone genes in rod-like photoreceptors. Additionally, Nr2e3 co-activates the transcription of rod-specific genes like Rho and Gnat1 along with Crx and Nrl.
The finding that partial reprogramming of rods to cones can reduce rod death and decrease secondary cone loss to spare cone-mediated vision in a mouse model of RP provides an approach to develop therapies for this disorder and other similar degenerative diseases. This pathway is also potentially amenable to manipulation pharmacologically, since Nr2e3, the downstream target of Nrl, is a nuclear hormone receptor, and probably capable of antagonism.
Despite the advances for treating retinal disease, a need exists for improved therapeutic agents and treatments. The present invention seeks to fulfill this need and provides further related advantages.